HIV/SIV infections lead to a breakdown of the integrity of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression can result in candidiasis, necrotizing gingivitis, periodontitis, hairy leukoplakia, increased oral tumors, and can also contribute to and predict distal disease complications elsewhere. ROR?t+ innate lymphoid cells type 3 (ILC3) produce IL-17 and IL-22 and are vital for maintaining the integrity of the GI epithelium, mediating mucosal antimicrobial defense and stability of commensal microflora, but others and we have recently shown massive, systemic alterations in ILC3 numbers and functions in the oral, reproductive and gastrointestinal mucosae (Li and Reeves, Front Immunol, 2013; Li et al., PLoS Path, 2014). Furthermore, in our unpublished preliminary data we show: 1. SIV infection induces a highly inflammatory and cytotoxic ILC3 phenotype in the oral cavity; 2. Efficient depletion in oral, colorectal, and vaginal mucosae using a novel ILC3-depleting antibody developed by our laboratory specifically for rhesus macaques. 3. Dysbiosis of specific microbial species is associated with chronic immune activation; and 4. Probiotic therapy reduces immune activation during SIV infection and induces expansion of functional ILC3 numbers in the mucosae. In this innovative and transformative proposal we will evaluate the core hypothesis that ILC3 act as a sensitive and targetable modulator for mucosal homeostasis, immune activation, and microflora in the oral cavity through three complementary specific aims: 1. Experimentally determine the role of ILCs in modulating the oral microbiome and oral mucosae homeostasis; 2. Define the kinetics, activation, and detailed immunologic effects of SIV infection on ILCs and microbiome in the oral cavity; and 3. Investigate the effects of probiotic therapy on oral ILCs and microbiome during chronic treated and untreated SIV infection.